Vaccines against human pathogens are sorely needed, but difficult to obtain. Few, if any, suitable methods or systems are available for exposing a human immune system to a human infectious agent or pathogen and obtaining useful information that can be used to design a suitable vaccine that induces immunity in a human subject to the infectious agent or pathogen of interest. It is often not ethical, nor practical, to expose human subjects to immunogens derived from a pathogen or an infectious agent in a protocol for designing a vaccine, and non-human animal systems are typically unsuitable for obtaining useful information about human immunogenicity.
Although humans can develop broadly neutralizing antibodies against infectious agents, and epitopes bound by such antibodies can be identified, the epitopes are paradoxically relatively ineffective as immunogens to induce immunity when used as vaccine candidates. This is because the epitopes recognized by broadly neutralizing antibodies are not the same epitopes that bind early stage antibodies, such as those present on early B cell receptors (BCRs) of the human immunoglobulin naïve repertoire. Thus, vaccinating a human subject with an immunogen that contains the epitope of a broadly neutralizing antibody may only rarely, if at all, result in any significant immunity to the infectious agent in the human subject. That is to say, identifying an important epitope that reacts with a broadly neutralizing antibody is, frequently, useless as a potential vaccine. This significant observation compels the conclusion that B cell clonal development toward mature B cells that express broadly neutralizing antibodies is driven by immunogens that are not identical to the epitope bound by the broadly neutralizing antibody. The problem, it seems, is complex and ties in with early B cell development.
In order to develop a rational process of creating effective vaccines from what is known of B cell development and the human immune response to human infectious agents, a suitable system is needed for the development of candidate vaccines—a system that allows assessment of how the human immune response interacts with immunogens and their variants to ultimately develop a B cell line that produces a broadly neutralizing antibody to an epitope of a human infectious agent or pathogen, and—in the process—to identify an immunogen variant that can serve as a vaccine that can induce broadly neutralizing antibodies in the general human population. The process involves a search for a key immunogen that can prime the naïve human immunoglobulin repertoire and, with judiciously selected boost immunogens, drive the B cell clonal selection process to produce a mature B cell that expresses broadly neutralizing antibodies.
There is a need in the art for compositions and methods for generating vaccines that are suitable for immunizing humans against human infectious agents. There is a need in the art for rational methods for designing immunogens to be used as vaccines in human subjects. There is a need in the art for humanized systems, e.g., humanized animals, that can be used in methods to generate vaccines and vaccine candidates to immunize humans against human infectious agents. There is a need for a non-human platform that can recapitulate a human B cell response, for making vaccines to infectious agents by promoting development of desirable B cells through the use of immunogen variants that will ultimately result in the development of desirable B cells that express broadly neutralizing antibodies against an infectious agent of interest. There is also a need to use humanized animals to further develop broadly neutralizing antibodies to epitopes of infectious agents.